The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse and the consequences of that abuse. Studies have indicated that: (1) the Dl dopamine receptor appears to be less involved in the subjective behavioral effects of cocaine in the monkey than was indicated in the rat. To better document this possible species difference several additional Dl dopamine receptor agonists will be studied. In addition, there is evidence that non-dopaminergic effects may be important components of the pharmacological profile cocaine. (2) The Dl dopamine-receptor mediated lethal effects of cocaine appear to principally involve peripheral rather than central nervous system mechanisms. (3) Differences in the involvement of postsynaptic dopamine receptors in the effects of various stimulants other than cocaine have been established. These differences involve a modulation of effects by GABAergic agents. (4) The tolerance that develops to the behavioral effects of cocaine does not confer cross tolerance to all dopamine uptake inhibitors. This tolerance is not related to changes in parameters of Dl and D2 dopamine receptors, nor to receptors at biogenic amine transport sites. In addition metabolic changes in the fate of cocaine contribute minimally, if at all, to the tolerance that develops to cocaine. (5) In collaboration with the Neuroscience Branch (N. Pilotte, J. Boja, M. Mitchell and M. Kuhar), studies have been conducted to further examine possible changes in neuroendocrine or receptor binding parameters in the rat with repeated cocaine injection. Ten days of repeated injections of cocaine causes a hyperprolactinemia, and increases neurotensin binding in the prefrontal cortex (where neurotensin is co-localized with dopamine). This effect persists for 10 days after the last injection of cocaine. Preliminary results also indicate that binding to the dopamine transporter is decreased in the nucleus accumbens 10 days after the last dose of cocaine. These results may relate to cocaine dependence, tolerance or sensitization and we plan to conduct experiments that relate these long-term neuronal effects of cocaine to behavior. (3) The synthetic chemistry component of the laboratory has synthesized pyrolysis products of cocaine that have been identified in crack-cocaine users. These compounds have some structural similarities to known cholinergic toxins. The pharmacology of these compounds is being characterized.